Heterogeneous Host Susceptibility Enhances Prevalence of Mixed-Genotype Micro-Parasite Infections

Dose response in micro-parasite infections is usually shallower than predicted by the independent action model, which assumes that each infectious unit has a probability of infection that is independent of the presence of other infectious units. Moreover, the prevalence of mixed-genotype infections was greater than predicted by this model. No probabilistic infection model has been proposed to account for the higher prevalence of mixed-genotype infections. We use model selection within a set of four alternative models to explain high prevalence of mixed-genotype infections in combination with a shallow dose response. These models contrast dependent versus independent action of micro-parasite infectious units, and homogeneous versus heterogeneous host susceptibility. We specifically consider a situation in which genome differences between genotypes are minimal, and highly unlikely to result in genotype-genotype interactions. Data on dose response and mixed-genotype infection prevalence were collected by challenging fifth instar Spodoptera exigua larvae with two genotypes of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), differing only in a 100 bp PCR marker sequence. We show that an independent action model that includes heterogeneity in host susceptibility can explain both the shallow dose response and the high prevalence of mixed-genotype infections. Theoretical results indicate that variation in host susceptibility is inextricably linked to increased prevalence of mixed-genotype infections. We have shown, to our knowledge for the first time, how heterogeneity in host susceptibility affects mixed-genotype infection prevalence. No evidence was found that virions operate dependently. While it has been recognized that heterogeneity in host susceptibility must be included in models of micro-parasite transmission and epidemiology to account for dose response, here we show that heterogeneity in susceptibility is also a fundamental principle explaining patterns of pathogen genetic diversity among hosts in a population. This principle has potentially wide implications for the monitoring, modeling and management of infectious diseases. Author Summary: What elements are indispensable in the description of the most basic host-pathogen interactions? The simplest models of infection generally fail to predict how many host plants or animals will become infected, and which virus genotypes will be present in these infected hosts. These simple models of infection are the building blocks for more complicated models of epidemiology and disease dynamics and diversity, making it important to identify the reasons for failure. We developed four probabilistic models of infection incorporating different mechanisms that could potentially explain and overcome this failure. We obtained experimental data to test these models by exposing Lepidopteran larvae to different genotypes of an insect DNA virus, and determining which virus genotypes had infected them. The model which best described the data added only one element: variation in the susceptibility of individual caterpillars to the virus. Host variation in susceptibility is known to affect transmission of viruses between hosts, but here we show it is inextricably linked to infection biology and indispensable for understanding pathogen diversity in host populations.